We have established a method for using synthetic oligonucleotides of mixed sequence as specific hybridization probes. These probes are mixtures of all possible coding sequences predicted from a short peptide sequence within a protein. Stringent hybridization criteria are used to select the single correct sequence from the mixture. Using this approach, we have isolated a cloned cDNA for human beta 2-microglobulin. We are currently screening libraries of cloned mouse cDNAs for H2Kb antigen clones. Methodologies have also been established for introducing mutational changes in DNAs cloned in pBR322 using oligonucleotides of defined sequence to direct the changes and screen for the mutants.